Protective Effects of anti-BclA Antibodies in Bacillus anthracis infection The use of Bacillus anthracis as a bioweapon in 2001 underlies the importance of understanding the mechanisms of pathogenesis of this ubiquitous bacterium. The mechanisms that have yet to be completely elucidated include uptake by the human host cells, germination of the spores in the host and the pathological consequences of the host response to the toxins elaborated by the vegetative cells within the host. Of particular interest are the mechanisms of spore entry into the host. This includes the nature of targeted cell types in the airways and subsequent initial spore encounter with cellular and humoral elements of the innate and adaptive immune response. An understanding of these spore-host interactions and the early immune response to the spores will allow the development of an interventional vaccine or drug strategy that would act prior to the germination of spores within the host and thus prevent development of Anthrax. In order to understand these interactions, most laboratories use A/J mice due to their natural susceptibility to the normally non-pathogenic Sterne strain. This limits the use of genetically modified mice currently available on the C57BL/6 background. In order to conduct our studies, we use a novel strategy in which we utilize C57BL6 C5-/- mice that we have proved susceptible to the Sterne strain in a manner similar to A/J mice. This allows the use of a more diverse panel of genetically modified mice to conduct Anthrax studies. We have also developed monoclonal antibodies specific to BclA, a major component of the B. anthracis exosporium. These highly specific antibodies have demonstrated protective in vivo effects in mice intratracheally infected with B. anthracis. We will establish the mechanisms of protection of these monoclonal antibodies, which may act via opsonization or direct killing. We will determine the role of exosporium-antibody Fc receptor interactions on protection against spore challenges. With this knowledge we will be able to identify potential mechanisms to rapidly inactivate spores prior to establishment of infectious loci and vegetative cell outgrowth resulting in death from toxemia and septicemia. Therapeutic strategies of this nature would be a major supplement to the current PA-based vaccines as well as to the current recommended antibiotic regimens and in the case of multi- resistant B. anthracis strains engineered to produce additional toxins. PUBLIC HEALTH RELEVANCE: The use of Bacillus anthracis spore dispersal as an agent of terrorism remains an important issue to both civilian and military personnel. The exosporium, being the outermost layer of the spore stage of this organism, is the first point of contact of spores with host cells. By defining the mechanisms of anti-spore antibody protection and the role surface receptors on host cells play, we may be able to develop interventional strategies to induce immune protection or drugs that will inactivate or destroy spores, thus preventing bacterial development, the elaboration of toxins, and death.